Adrenal Cortical Carcinoma Associated With Lynch Syndrome: A Case Report and Review of Literature
Ravinder Jeet Kaur,1 Pavel N. Pichurin,2 Jolaine M. Hines,3 Ravinder J. Singh,4 Stefan K. Grebe,4 and Irina Bancos1
1Division of Endocrinology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905; 2Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota 55905; 3Immunochemical Core Laboratory, Mayo Clinic, Rochester, Minnesota 55905; and 4Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905
ORCID numbers: 0000-0001-6445-2776 (R. J. Kaur).
Objective: Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. ACC was re- ported in 3.2% patients with Lynch syndrome (LS), however no particular case-detection strategies have been recommended.
Participants: We report a case of a 65-year-old woman who was incidentally discovered with a large adrenal mass during work-up of postmenopausal uterine bleeding. She was recently diagnosed with MSH6 germline mutation after her sister presented with uterine carcinoma in the setting of LS.
Results: Whereas the patient was asymptomatic for overt hormonal excess, biochemical work-up confirmed glucocorticoid autonomy and androgen and estrogen excess. Urine steroid profiling was suggestive of ACC. Adrenalectomy confirmed an oncocytic ACC with focal extracapsular extension into the periadrenal adipose tissue with a Ki-67 of 15% and a peak mitotic count of 40/50 high-power fields.
Conclusion: ACC can be the only manifestation of LS. A best case-detection approach for ACC in the asymptomatic patient with LS is unclear, however urine steroid profiling could be considered.
Copyright @ 2019 Endocrine Society
This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).
Freeform/Key Words: Lynch syndrome, adrenocortical carcinoma, adrenocorticotropic hormone, steroid profiling, diagnosis
Adrenal cortical carcinoma (ACC) is a rare malignancy with an incidence of one to two per one million individuals per year but represents ~13% of adrenal tumors >4 cm in referral en- docrine centers [1]. ACC occurs most frequently in the fifth to sixth decade of life and demonstrates a female-to-male predominance of 2.5 to 1. Although most ACCs are sporadic, these can also occur as part of an hereditary syndrome, such as Li-Fraumeni syndrome, multiple endocrine neoplasia type 1, Beckwith-Wiedemann syndrome, familial adenopoly- matosis, neurofibromatosis type 1, Carney complex, and Lynch syndrome (LS) [2]. Despite the large tumor size on presentation, approximately one-half of patients with ACC is discovered incidentally (42%), with a smaller proportion of patients presenting with hormonal excess (31%) or with symptoms of mass effect (20%) or discovered during cancer-staging imaging for another malignancy (6%) and during evaluation of B symptoms (1%) [3]. Early discovery is key to assure a better prognosis.
Abbreviations: ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; LS, Lynch syndrome.
LS-hereditary nonpolyposis colorectal cancer is an autosomal-dominant hereditary cancer predisposition syndrome caused by germline pathogenic variants in any of DNA mismatch repair genes [4], including MLH1, MSH2, MSH6, and PMS2 [5]. Patients with LS demonstrate a substantial lifetime risk of developing colorectal (80%) and endometrial cancer (60%) [4, 6]. Germline pathogenic variants in the MSH6 gene account for ~18% of LS cases [7]. Association of ACC with LS has been reported only in several case reports and one small prospective study, totaling 12 patients (Table 1) [5, 8-14].
1. Case Report
A 65-year-old woman with a past medical history of hypertension presented for evaluation of a recently developed vaginal bleeding. Transvaginal ultrasound demonstrated endometrial thickening and two uterine fibroids. The patient was treated with dilation and curettage of endometrial hyperplasia, and pathology was benign. Incidentally, on the same initial ultrasound, a large heterogeneous mass within the right upper quadrant of the abdomen was also noted. To investigate this finding further, an abdominal CT scan was performed and revealed a heterogeneous right adrenal mass, 6.0 × 5.1 × 7.8 cm (Fig. 1A). The patient was referred to the Mayo Clinic for further evaluation of the right adrenal mass.
Notably, as a result of a recent diagnosis of LS in the patient’s sister, our patient was tested positive for familial pathogenic variant in MSH6. A recent colonoscopy was normal.
A. Investigations
During evaluation in the adrenal clinic, the patient was mostly asymptomatic, although she did complain of some fatigue, loss of appetite, and a 3-pound weight loss over the prior 2 weeks (which she thought was a result of anxiety related to the recent diagnosis of the adrenal mass). On physical examination, she did not have Cushingoid features, acne, or hirsutism. Her blood pressure was 135/83 mmHg, and no clinical features suggestive of primary hyperaldosteronism, such edema or hypokalemia, were present. Biochemical work-up was negative for pheochromocytoma but demonstrated evidence of androgen excess, elevated serum steroid precursors, and estrogen excess, which could have explained the patient’s recent uterine bleeding (Table 2). In addition, the patient dem- onstrated evidence of adrenocorticotropic hormone (ACTH) independent cortisol excess based on abnormal cortisol concentrations after 1 mg overnight dexamethasone ad- ministration, along with low ACTH and elevated 24-hour, urine-free cortisol (Table 2). Urine multisteroid profiling was performed and was highly suspicious for ACC (Table 2). Based on the clinical, biochemical, and imaging presentation, ACC was suspected, and adrenalectomy was recommended.
B. Treatment
Patient was treated with an open right adrenalectomy. Final pathology demonstrated a 9.2 X 5.9 × 4.8-cm adrenal oncocytic ACC (Fig. 1B) with focal extracapsular extension into per- iadrenal adipose tissue, a Ki-67 index of 15%, and a peak mitotic count of 40 mitoses in 50 high-powered fields. Surgical margins were negative for tumor. Postoperatively, the patient was treated with glucocorticoid-replacement therapy, and treatment with mitotane was started 6 weeks after surgery.
C. Outcome and Follow-Up
During the subsequent 26-months of follow-up, the patient remains in remission: imaging demonstrates no evidence for local recurrence or metastatic disease. In addition, patient’s serum and urinary steroid biomarkers are within normal ranges.
| Studies | Age | Sex | MSH Type | Microsatellite Stability | Mode of Discovery | Tumor Size, mm | Adrenal Hormone Excess | Treatment | Mitotic Count | Outcome | Criteria |
|---|---|---|---|---|---|---|---|---|---|---|---|
| [8] | 44 | M | NR | NR | NR | NR | NR | NR | NR | Died of disease | NR |
| [9] | 65 | F | MSH2 | MSS | Cushingoid features | NR | ACTH-independent Cushing | S | 130/50 HPF | Died of disease | Didn't meet Amsterdam criteria |
| [10] | 34 | M | MSH2 | MSS | Symptoms of hypertension and hypokalemia (possible primary hyperaldosteronism) leading to imaging) | 40 | NR (possible primary hyperaldosteronism) | S | NR | Died of disease | Met Amsterdam criteria II |
| [11] | 60 | F | MSH2 | MSS | Follow-up MRI for breast cancer | 51 | NR | S | NR | Alive | Met Amsterdam criteria |
| [5] | 29 | M | MSH2 | MSS | Flank pain | NR | NR | S | 20/50 HPF | Alive | NR |
| [12] | 52 | M | MSH2 | MSS | Genetic evaluation | NR | NR | NR | NR | Alive | Met Amsterdam criteria I |
| 47 | M | MLH1 | MSS | Genetic evaluation | NR | NR | NR | NR | Alive | Met Amsterdam criteria I | |
| 39 | M | MSH6 | MSS | Genetic evaluation | NR | NR | NR | NR | Alive | NR | |
| 42 | F | MSH2 | MSS | Genetic evaluation | NR | NR | NR | NR | Alive | NR | |
| 23 | F | MSH2 | NR | Genetic evaluation | NR | NR | NR | NR | Alive | NR | |
| [13] | 54 | F | MSH2 | NR | Lion pain, weight loss, and lethargy | 140 | None | S | 1/50 HPF | Alive | Met Amsterdam criteria II |
| [14] | 68 | M | MSH2 | NR | Abdominal pain | 41(Extra adrenal) | S | 2/10 HPF | Alive | Met Amsterdam criteria II | |
| This study | 65 | F | MSH6 | NR | Incidental discovery | 92 | Androgen, estrogen excess | S | 40/50 HPF | Alive | NR |
Abbreviations: ACTH, adrenocorticotropic hormone; F, female; HPF, high-power field; M, male; MSS, microsatellite stable; NR, not reported; S, surgical.
(a)
(b)
METRIC 1 2 3 4 5 6
2. Discussion
We present a rare case of a patient with LS whose only presentation was incidentally dis- covered ACC. Outside from ACC, she had no other manifestations of LS at the time of this case report.
Only 13 cases (including our case) have been reported so far in the literature (Table 1). The median age of presentation was 47 years (range: 23 to 68), and 46% were women. The first association of ACC with LS was described in the “N family” of two large Midwestern kindreds by H. T. Lynch in 1966 [8]. Proband from the N family died at age 44 from ACC, whereas his siblings presented with multiple primary colon carcinomas, endometrium carcinomas, and other cancers [8]. Later, three other case reports demonstrated an association of ACC with LS in patients with the MSH2 germline mutation [5, 10, 11]. In 2013, a prospective study of 114 patients with ACC demonstrated a 3.2% prevalence of LS, which is higher than in the general population (0.2%) and comparable to the prevalence of LS in patients with colorectal cancer and endometrial cancer (1% to 5%) [12]. In this study, five of 114 patients with ACC and LS had MSH2 (in three patients), MSH6 (one patient), and MLH1 (one patient) germline mutations, with four patients demonstrating microsatellite stability. More recently, two more case reports published in 2016 and 2018 [13, 14] again showed association between LS and ACC with MSH2 germline mutation.
It is challenging to diagnose ACC early in an asymptomatic phase, before substantial growth and metastases occur. The diagnosis of ACC is based on clinical presentation and imaging characteristics of adrenal mass (Hounsfield units >10, size >4 cm, and heteroge- neous). In patients with a genetic predisposition of ACC (such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia type 1, familial adenomatous
| Laboratory Test | Before Surgery | 1 Mo After Surgery | Reference Range |
|---|---|---|---|
| 24-h Urine | |||
| Urine-free cortisol, µg/24 h | 68 | N/A | 3.5-45 |
| Serum | |||
| ACTH, pg/mL | <5 | N/A | 7.2-63 |
| 8 AM Serum cortisol following | 13 | N/A | <1.8 |
| 1 mg overnight dexamethasone suppression test, µg/dL | |||
| Aldosterone, ng/dL | 20 | N/A | ≤21 |
| Renin plasma activity, ng/ml/h | 2 | N/A | 0.6-3.0 |
| Androstenedione, ng/dL | 151 | N/A | 30-200 |
| DHEA sulfate, µg/dL | 403 | <15 | <15-157 |
| 17-Hydroxyprogesterone, ng/dL | 167 | <40 | <51 |
| 17-Hydroxypregnenolone, ng/dL | 888 | <16 | 31-455 |
| Total testosterone, ng/dl | 30 | <7 | 8-60 |
| Estradiol, pg/mL | 113 | <10 | <10 (Postmenopausal) |
Abbreviations: DHEA, dehydroepiandrosterone; N/A, not available.
polyposis, neurofibromatosis 1, and LS), the incidence of ACC, although much higher than the general population, is still low to warrant serial imaging. Steroid profiling (Fig. 2) is an attractive alternative that could help diagnose ACC much earlier in the natural history of the disease [15]. In our patient, steroid profiling confirmed our suspicion of ACC after discovery of adrenal mass [16]. Whereas in this case, steroid profiling did not change our management,
Cholesterol
CYP11A]
Pregnenolone
CYP17A1
17OH-Pregnenolone
CYP17A1
Dehydroepiandrosterone
SULT2A1
DHEA-S
SPD
5PT
HSD3B2
HSD3B2
HSD3B2
DHEA
16a-DHEA
Etio
An
CYP17AI
CYP17AJ
17OH-Progesterone
Androstenedione
CYP19A1
Progesterone
Estrone
PD
CYP11B1
PT
17HP
11B-OH-AN
CYP21A2
CYP21A2
HSD17B
11-OXO-ET 11B-OH.ET
11-deoxycorticosterone
21-deoxycortisol
PTONE
Testosterone
CYPIIB?
THDOC
11-deoxycortisol
CYP19A1
SRDSA2
THS
An Etio
Estradiol
Corticosterone
CYP11B]
Dihydrotestosterone
CYP11B2
THB
Cortisol
THE
Sa-THF
An
18OH-corticosterone
HSD11B]
HSD11B2
LEGEND:
CYP11B2
6B-OH- cortisol
Cortisone
B-cortol
Z score
Greatly Elevated
Aldosterone
>10
THE
+5 to +10
Elevated
a-cortolone
B-cortolone
+2 to +5
Mildly elevated
-2 to +2
Normal
included in HRAM metabolite panel
enzyme
after appropriate validation, this test could be offered as a case-detection, noninvasive, and radiation-free test to patients at high risk for ACC. Surgical resection is the mainstay of treatment of ACC with a goal to achieve a microscopic tumor clearance (R0) resection. Further management depends on the stage of ACC and prognostic markers derived from pathology examination.
3. Conclusion
In summary, we present a patient with LS whose only manifestation was ACC, adding to the available literature of only 12 cases. We also demonstrated that steroid profiling could serve as a noninvasive diagnostic and potentially as a case-detection tool for patients at risk for ACC.
Acknowledgments
Correspondence: Irina Bancos, MD, Division of Endocrinology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: Bancos.Irina@mayo.edu.
Disclosure Summary: The authors have nothing to disclose.
References and Notes
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